Hepatotoxicity

Overview

• INH, Rifampin, and PZA all are associated with DILI (drug-induced liver injury)

• Only one case of DILI has been reported for Ethambutol

• Fluoroquinolones are rare causes of DILI• Risk of DILI in active TB treatment studies

ranges from 5 to 33%

Saukkonen JJ, ATS Statement: Hepatotoxicity of antiTB Rx. Am J Respir Crit Care Med, 2006

INH

• Probably the most common cause of TB DILI• Age related, ?pregnancy related, daily ETOH

may increase risk 4 fold• Concomitant use of Rifampin increases the

risk

Kaplowitz N. Drug-induced liver injury. CID, 2004

Rifampin

• Occasionally causes interference with bilirubin uptake resulting in sub-clinical or overt jaundice. This may be transient.

• Rarely causes hepatocellular injury when used alone

• Meta-analysis of INH + Rifampin estimated a risk of DILI of 2.55%

• Rifapentine is similar, but rifabutin has < risk

Steele MA. Toxic hepatitis with INH and Rif: a meta-analysisi. Chest, 1991

PZA

• When used with rifampin, EMB, or a fluoroquinolone for treatment of LTBI, DILI has been reported in 18-58% of cases

• When used as part of RIPE, incidence much lower

• Dose and duration dependent• Can induce DRESS syndrome or

granulomatous hepatitis

ATS/CDC. Targeted testing and treatment of LTBI, 2000

Approach to patient with DILI

• Stop meds! if AST/ALT > 5X normal if asymptomatic, and >3X normal if symptomatic

• For fulminant disease, consider N-acetyl cysteine

• Consider other causes of hepatotoxicity• Follow AST/ALT weekly and when < 2X

normal, rechallenge

Rechallenge after DILI

• Begin Ethambutol + INH or Rifampin– Pattern and timing of LFT abnormalities can help– In most cases it will be EMB + Rif

• Allow 3-5 days before adding in next drug• PZA should generally be added last and you

may decide not to rechallenge.

High Risk for DILI

• Chronic ETOH, chronic hep B/C, hx. of abn. LFTs, taking other hepatotoxic meds, +/- pregnant/ 3 mos. postpartum

• Initiate standard RIPE, but follow closely (q 2-4 weeks) with ALT/AST

Pre-existing liver dysfunction

• Caveat: Abnormal LFTs in disseminated TB can be related to the TB and will improve with standard RIPE

• Baseline LFTs > 3X upper limit of normal (ULN)– strongly consider use of regimen with 2, not 3

hepatotoxic drugs: INH/Rif/EMB, PZA/RIF/EMB• Presence of cirrhosis– strongly consider use of only one hepatotoxic

drug: Rif/EMG/and +/- levo, moxi, or cycloserine

Pre-existing liver dysfunction

• Presence of active, acute hepatitis (ETOH or viral) or hepatic encephalopathy– Initiate treatment with EMB, fluoroquinolone, and

injectable (usually Strep but can use Amikacin or Capreomycin) +/- cycloserine

– If and when LFTs normalize to < 2 ULN, add in standard drugs as tolerated